Neurorestoration Group, Wolfson Centre for Age-Related Diseases, King's College London, London, UK.
Gene Ther. 2012 Jan;19(1):49-60. doi: 10.1038/gt.2011.71. Epub 2011 May 12.
The corticospinal tract (CST) is extensively used as a model system for assessing potential therapies to enhance neuronal regeneration and functional recovery following spinal cord injury (SCI). However, efficient transduction of the CST is challenging and remains to be optimised. Recombinant adeno-associated viral (AAV) vectors and integration-deficient lentiviral vectors are promising therapeutic delivery systems for gene therapy to the central nervous system (CNS). In the present study the cellular tropism and transduction efficiency of seven AAV vector serotypes (AAV1, 2, 3, 4, 5, 6, 8) and an integration-deficient lentiviral vector were assessed for their ability to transduce corticospinal neurons (CSNs) following intracortical injection. AAV1 was identified as the optimal serotype for transducing cortical and CSNs with green fluorescent protein (GFP) expression detectable in fibres projecting through the dorsal CST (dCST) of the cervical spinal cord. In contrast, AAV3 and AAV4 demonstrated a low efficacy for transducing CNS cells and AAV8 presented a potential tropism for oligodendrocytes. Furthermore, it was shown that neither AAV nor lentiviral vectors generate a significant microglial response. The identification of AAV1 as the optimal serotype for transducing CSNs should facilitate the design of future gene therapy strategies targeting the CST for the treatment of SCI.
皮质脊髓束（CST）被广泛用作评估增强脊髓损伤（SCI）后神经元再生和功能恢复的潜在治疗方法的模型系统。然而，CST 的高效转导仍然具有挑战性，需要进一步优化。重组腺相关病毒（AAV）载体和整合缺陷型慢病毒载体是用于中枢神经系统（CNS）基因治疗的有前途的治疗性递送系统。在本研究中，评估了七种 AAV 载体血清型（AAV1、2、3、4、5、6、8）和整合缺陷型慢病毒载体对皮质内注射后皮质脊髓神经元（CSN）的细胞嗜性和转导效率，以确定其将 GFP 转导到穿过颈脊髓背侧 CST（dCST）的纤维中的能力。AAV1 被鉴定为转导皮质和 CSN 的最佳血清型，GFP 表达可检测到穿过颈脊髓背侧 CST（dCST）的纤维中。相比之下，AAV3 和 AAV4 对 CNS 细胞的转导效率较低，AAV8 则可能对少突胶质细胞具有潜在的嗜性。此外，研究表明 AAV 或慢病毒载体均不会引起明显的小胶质细胞反应。AAV1 被鉴定为转导 CSN 的最佳血清型，这应该有助于设计针对 CST 的未来基因治疗策略，以治疗 SCI。
